[HTML][HTML] β-Catenin is required for intrinsic but not extrinsic BCR-ABL1 kinase-independent resistance to tyrosine kinase inhibitors in chronic myeloid leukemia

AM Eiring, JS Khorashad, DJ Anderson, F Yu… - Leukemia, 2015 - nature.com
AM Eiring, JS Khorashad, DJ Anderson, F Yu, HM Redwine, CC Mason, KR Reynolds…
Leukemia, 2015nature.com
Activation of nuclear β-catenin and expression of its transcriptional targets promotes chronic
myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and
leukemic stem cell self-renewal. We report that nuclear β-catenin has a role in leukemia cell-
intrinsic but not-extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib
inhibition of BCR-ABL1 kinase activity, β-catenin expression was maintained in intrinsically
resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) …
Abstract
Activation of nuclear β-catenin and expression of its transcriptional targets promotes chronic myeloid leukemia (CML) progression, tyrosine kinase inhibitor (TKI) resistance, and leukemic stem cell self-renewal. We report that nuclear β-catenin has a role in leukemia cell-intrinsic but not-extrinsic BCR-ABL1 kinase-independent TKI resistance. Upon imatinib inhibition of BCR-ABL1 kinase activity, β-catenin expression was maintained in intrinsically resistant cells grown in suspension culture and sensitive cells cultured in direct contact (DC) with bone marrow (BM) stromal cells. Thus, TKI resistance uncouples β-catenin expression from BCR-ABL1 kinase activity. In β-catenin reporter assays, intrinsically resistant cells showed increased transcriptional activity versus parental TKI-sensitive controls, and this was associated with restored expression of β-catenin target genes. In contrast, DC with BM stromal cells promoted TKI resistance, but had little effects on Lef/Tcf reporter activity and no consistent effects on cytoplasmic β-catenin levels, arguing against a role for β-catenin in extrinsic TKI resistance. N-cadherin or H-cadherin blocking antibodies abrogated DC-based resistance despite increasing Lef/Tcf reporter activity, suggesting that factors other than β-catenin contribute to extrinsic, BM-derived TKI resistance. Our data indicate that, while nuclear β-catenin enhances survival of intrinsically TKI-resistant CML progenitors, it is not required for extrinsic resistance mediated by the BM microenvironment.
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